Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.
Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.
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DOI：
10.1161/circgenetics.113.000126
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发表时间：
2013-06
期刊：
影响因子：
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通讯作者：
Williams SM
中科院分区：
文献类型：
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作者：
Predazzi IM;Rokas A;Deinard A;Schnetz-Boutaud N;Williams ND;Bush WS;Tacconelli A;Friedrich K;Fazio S;Novelli G;Haines JL;Sirugo G;Williams SM
自然选择塑造了许多人类基因，包括一些与复杂疾病有关的基因。了解选择如何影响基因，特别是多效性基因，可能对评估疾病关联和环境变化所起的作用很重要。这可能是特别感兴趣的基因拮抗作用，导致不同的选择模式。由OLR 1编码的凝集素样低密度脂蛋白1受体（LOX-1）是示例性的。它在心血管和免疫系统中具有拮抗作用，因为相同的蛋白质结构域结合氧化LDL和细菌细胞壁蛋白-前者有助于动脉粥样硬化，后者可能保护免受感染。我们在人类和非人类灵长类动物中研究了该基因的选择模式，以确定变量选择是否会导致CVD关联研究中的相互矛盾的结果。我们分析了来自11种非人灵长类物种的序列以及来自多个人类群体的SNP和序列数据。结果表明，衍生的等位基因在灵长类谱系中是有利的（可能是由于最近的正选择）。然而，衍生和祖先的等位基因在人类群体中，特别是欧洲人中得以保留（可能是由于LOX-1的双重作用产生的平衡选择）。平衡选择可能反映了人类对不同环境压力的反应。这些数据表明，不同的选择模式，内和物种之间，在OLR 1关联研究难以复制，即使该基因的病因与CVD。选择分析可以识别出表现出基因-环境相互作用的基因，这些基因对于解开疾病关联至关重要。
Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin like low-density lipoprotein 1 receptor (LOX-1), encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems as the same protein domain binds oxidized LDL and bacterial cell wall proteins - the former contributing to atherosclerosis, the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and non-human primates, to determine whether variable selection can lead to conflicting results in CVD association studies. We analyzed sequences from 11 non-human primate species as well as SNP and sequence data from multiple human populations. Results indicate that the derived allele is favored across primate lineages (probably due to recent positive selection). However, both the derived and ancestral alleles were maintained in human populations, especially European ones (possibly due to balancing selection derived from LOX-1's dual roles). Balancing selection likely reflects response to diverse environmental pressures among humans. These data indicate that differential selection patterns, within and between species, in OLR1 render association studies difficult to replicate even if the gene is etiologically connected to CVD. Selection analyses can identify genes exhibiting gene-environment interactions critical for unraveling disease association.